Inhibitors of bruton's tyrosine kinase

1. A method of treating a mast cell proliferative disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound that irreversibly inhibits an interleukin-2 inducible tyrosine kinase (ITK) having the structure of Formula (A1)

wherein:

A is N;

R 1 is L 2 -(substituted or unsubstituted heteroaryl), or L 2 -(substituted or unsubstituted aryl), where L 2 is a bond, O, S, —S(═O), —S(═O) 2 , C(═O), -(substituted or unsubstituted C 1 -C 6 alkylene), or -(substituted or unsubstituted C 2 -C 6 alkenylene);

R 2 and R 3 are independently selected from H or lower alkyl;

R 4 is L 3 -X-L 4 -G, wherein,

L 3 is optional, and when present is a bond, or an optionally substituted group selected from alkylene, heteroalkylene, arylene, heteroarylene, alkylarylene, alkylheteroarylene, and alkylheterocycloalkylene;

X is optional, and when present is a bond, O, —C(═O), S, —S(═O), —S(═O) 2 , —NH, —NR 9 , —NHC(O), —C(O)NH, —NR 9 C(O), —C(O)NR 9 , —S(═O) 2 NH, —NHS(═O) 2 , —S(═O) 2 NR 9 —, —NR 9 S(═O) 2 , —OC(O)NH—, —NHC(O)O—, —OC(O)NR 9 —, —NR 9 C(O)O—, —CH═NO—, —ON═CH—, —NR 10 C(O)NR 10 —, heteroarylene, arylene, —NR 10 C(═NR 11 )NR 10 —, —NR 10 C(═NR 11 )—, —C(═NR 11 )NR 10 —, —OC(═NR 11 )—, or —C(═NR 11 )O—;

L 4 is optional, and when present is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted heterocyclene;

or L 3 , X and L 4 taken together form a nitrogen containing heterocyclic ring;

G is

wherein,

R a is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;

R 7 and R 8 are H; and R 6 is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylether, C 1 -C 8 alkylamide, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or

R 6 and R 8 are H; and R 7 is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 8 alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C 1 -C 8 alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylether, C 1 -C 8 alkylamide, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or

R 7 and R 8 taken together form a bond; and R 6 is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C i -C g alkylaminoalkyl, C 1 -C 8 hydroxyalkylaminoalkyl, C i -C g alkoxyalkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkylC 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted heteroaryl, C 1 -C 4 alkyl(aryl), C 1 -C 4 alkyl(heteroaryl), C 1 -C 8 alkylether, C 1 -C 8 alkylamide, or C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl);

R 9 is selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;

each R 10 is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or

two R 10 groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or

R 10 and R 11 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or

R 11 is selected from H, —S(═O) 2 R 8 , —S(═O) 2 NH 2 , —C(O)R 8 , —CN, —NO 2 , heteroaryl, or heteroalkyl; or a pharmaceutically acceptable solvate, hydrate, or salt thereof.

2. The method of claim 1 wherein cells of the mast cell proliferative disorder express ITK.

3. The method of claim 1 wherein cells of the mast cell proliferative disorder express Bruton's tyrosine kinase (BTK).

4. The method of claim 1 wherein R 2 and R 3 are each independently H.

5. The method of claim 1 wherein R 1 is a substituted phenyl.

6. The method of claim 1 wherein L 3 , X and L 4 taken together form a nitrogen containing heterocyclic ring.

7. The method of claim 6 wherein G is

or

8. The method of claim 1 wherein R 6 , R 7 , and R 8 are each independently H.

9. The method of claim 1 wherein the compound has the structure

10. A method for treating a mast cell proliferative disorder comprising administering to a subject in need thereof an irreversible inhibitor of an interleukin-2 inducible tyrosine kinase (ITK), wherein the inhibitor is a compound having the structure of

or a pharmaceutically acceptable solvate, hydrate, or salt thereof.